Passive immunization, the administration of pre-formed antigen-specific antibody, provides considerable advantages over active immunization as an immune state can essentially be provided on demand with a lessened chance of an inadequate response or side effects. While passive immunization has proven benefits for peripheral challenge, it is problematic for neurotrophic pathogens because of the blood-brain barrier (BBB), a specialization of the neurovasculature that protects CMS tissues from circulating cells and factors including antibodies. As is apparent from the number of neurotrophic viruses classified as NIAID priority pathogens, these are particularly suitable for bioterrorism. Included among this group is rabies virus (RV), which due to the emergence of bat RV variants that cause rabies in humans without overt evidence of exposure, has become a greater threat for use as a bioweapon. Rabies has a long history of successful post-exposure prophylaxis using a combination of passive and active immunization. The possibility that similar but improved therapies may be useful for bat-RV and other neurotrophic viruses prompts the need for a better understanding of the mechanisms of post-exposure prophylaxis. Clearance of RV from the infected CMS requires the administration of particular subsets of neutralizing antibodies as well as some aspect of the adaptive immune response which we speculate is the induction of blood-brain barrier (BBB) permeability. Using adoptive transfer of isolated, congenic T and B cell subsets into gene knockout mice that fail to mediate blood-brain barrier (BBB) permeability changes when infected with RV, we will identify the cell type(s) responsible for the loss of BBB integrity as well as the mechanisms involved. By transfer of known protective RV-specific antibodies engineered to express different Ig heavy chains, chemically prepared antibody fragments, or B cells into RV-infected, B cell-deficient mice, we will determine the structure of rabies-neuroprotective antibodies and the means of their delivery to the CMS. The ultimate aim of this project is to provide a protocol whereby exposure to neurotrophic viruses can be treated by passive immunization when contact with the agent is imminent or has recently occurred.